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Clinic Rev Allerg Immunol (2012) 42:7178
DOI 10.1007/s12016-011-8291-x
Leaky Gut and Autoimmune Diseases
Alessio Fasano
Published online: 23 November 2011# Springer Science+Business Media, LLC 2011
Abstract Autoimmune diseases are characterized by tissue damage and loss of function due to an immune response that is directed against specific organs. This review is focused on the role of impaired intestinal barrier function on autoimmune pathogenesis. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin is the only physiologic modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/ immune response balance. When the zonulin pathway is deregulated in genetically susceptible individuals, autoimmune disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing the zonulin-dependent intestinal barrier function. Both animal models and recent clinical evidence support this new paradigm and provide the rationale for innovative approaches to prevent and treat autoimmune diseases.
Keywords Antigens . Autoimmunity . Gut permeability. Immune response . Tight junctions . Zonulin
Introduction
The intestinal epithelium is the largest mucosal surface providing an interface between the external environment and the mammalian host. Its exquisite anatomical and functional arrangements and the finely-tuned coordination of digestive, absorptive, motility, neuroendocrine, and immunological functions are testimonial of the complexity of the gastrointestinal (GI) system. Also pivotal is the regulation of molecular trafficking between the intestinal lumen and the submucosa via the paracellular space. The dimensions of the paracellular space are estimated to be between 10 and 15 , suggesting that under physiological circumstances, solutes with a molecular radius exceeding 15 (~3.5 kDa) will be excluded from this uptake route. Macromolecule trafficking is dictated mainly by intestinal paracellular permeability, whose regulation depends on the modulation of intercellular tight junctions (TJ). A fast growing number of diseases, including autoimmune diseases, are recognized to involve alterations in intestinal permeability related to changes in TJ competency.
Classical Theories on the Pathogenesis of Autoimmune
Diseases
Soon after autoimmune diseases were first recognized more than a century ago, it...